Novel silyl ester azetidine-2-sulfenate intermediates and process for preparing desacetoxycephalosporins

ABSTRACT

A penicillin sulfoxide is heated in the presence of silylating agent to produce a novel silyl ester azetidine-2-sulfenate which, by treatment with acid, is converted to a desacetoxycephalosporin compound.

CROSS REFERENCE

This application is a continuation-in-part of application Ser. No.640,606 filed Dec. 15, 1975, now abandoned, which is acontinuation-in-part of application Ser. No. 252,078 filed May 10, 1972,and now abandoned.

BACKGROUND OF THE INVENTION

The semi-synthetic production of a 7-acylamidodesacetoxycephalosporinantibiotic from a penicillin starting material has been of exceptionalimportance since the advent of the invention of Morin and Jackson (U.S.Pat. No. 3,275,626) who describe and claim a process for converting apenicillin sulfoxide ester to a desacetoxycephalosporanic acid ester.Subsequently, improvements were made upon this Morin-Jackson process.Robin D. G. Cooper found that the use of certain tertiary carboxamidesolvents (British Pat. No. 1,204,972) or certain tertiary sulfonamidesolvents (British Pat. No. 1,204,394) directed the heat rearrangement ofthe penicillin sulfoxide esters more specifically toward production ofthe corresponding desacetoxycephalosporin esters and permitted the useof lower temperatures. Hatfield (U.S. Pat. No. 3,591,585) improved uponthe Cooper contributions by finding that the conversion of a penicillinsulfoxide ester to a desacetoxycephalosporin ester by heating under acidconditions in the presence of a tertiary carboxamide solvent can befurther improved by carrying out the reaction in the presence of both asulfonic acid and means for removing or inactivating water present inthe reaction mixture.

The mechanism which is postulated in U.S. Pat. No. 3,275,626 for theconversion of the penicillin sulfoxide ester to adesacetoxycephalosporanic acid ester is by formation of a sulfenic acidinvolving scission of the S-C₂ bond. This mechanism has now beenconclusively established, and it furthermore has been shown (R. D. G.Cooper, J.A.C.S, 92, (1970) pp. 5010-5011) that, under the conditions ofreaction, a thermal equilibrium between the sulfoxide starting materialand the sulfenic acid intermediate is established. One approach whichwould be advantageous in accomplishing the desired conversion of apenicillin sulfoxide or ester derivative thereof to its correspondingdesacetoxycephalosporanic acid or ester derivative would be to trap thefleeting and unstable sulfenic acid intermediate in the form of a stableand isolatable intermediate. This intermediate could then be isolatedand subsequently converted to the corresponding desacetoxycephalosporinor could be formed under conditions which, without isolation, wouldpermit a virtual immediate conversion to the correspondingdesacetoxycephalosporin.

SUMMARY OF THE INVENTION

It is an object of this invention to provide compounds which are stableand isolatable intermediates in the conversion of penicillin sulfoxidesor esters thereof to their corresponding desacetoxycephalosporanic acidsor esters thereof.

It is also an object of this invention to provide a process forconverting penicillin sulfoxides or esters thereof to theircorresponding desacetoxycephalosporanic acids or esters thereof.

DETAILED DESCRIPTION OF THE INVENTION

Broadly, this invention relates to novel silyl ester compounds producedfrom penicillin sulfoxides. These silyl esters exhibit a sufficientdegree of stability to render them isolatable and amenable tocharacterization. The silyl esters of this invention have the formula:##STR1##

In the above formula the silicon atom is bonded to three groupscharacterized as R₁. Each R₁ independently is defined as C₁ -C₄ alkyl orphenyl. R₁ preferably is methyl or phenyl and, most preferably, ismethyl. Typical of the silyl radicals which can be present in the novelester intermediates of this invention are trimethylsilyl,triphenylsilyl, methyldiethylsilyl, propyldimethylsilyl, and the like.Generically, the esters of this invention can be named as silyl estersof azetidine-2-sulfenates.

The group R₂ in the above formula is a carboxy protecting group. Suchgroups and their use are well known in the penicillin and cephalosporinarts and need no specific exemplification since the man skilled in theart is well aware of the large number of groups which are available.Preferred carboxy protecting groups include, for example, C₁ -C₆ alkyl,2,2,2-trihaloethyl, 2-iodoethyl, benzyl, nitrobenzyl, tetrahydropyranyl,9-fluorenyl, succinimidomethyl, phthalimidomethyl, methoxybenzyl,dimethoxybenzyl, cyanomethyl, nitrophenyl, dinitrophenyl,2,4,6-trinitrophenyl, bis(p-methoxyphenyl)methyl, triphenylmethyl,benzhydryl, benzyloxymethyl, C₂ -C₆ alkanoyloxymethyl, C₂ -C₄ alkanoyl,phenacyl, or a radical of the formula ##STR2## in which each R₁ is asdefined hereinabove, and the like.

Especially preferred carboxy protecting groups include C₁ -C₆ alkyl,2,2,2-trihaloethyl, benzyl, nitrobenzyl, methoxybenzyl, benzhydryl, C₂-C₆ alkanoyloxymethyl, phenacyl, or a radical of the formula ##STR3## inwhich R₁ is methyl or phenyl.

In the above formula, R₃ and R₄ denote an amino protecting group. Suchgroups and their use are now well recognized in the penicillin andcephalosporin art and need no specific exemplification. Preferred aminoprotecting groups include, for example, the combination of R₃ beinghydrogen and R₄ being C₁ -C₈ alkanoyl; azidoacetyl; cyanoacetyl;haloacetyl; ##STR4## in which Ar is phenyl, thienyl, furyl, pyrrolyl, orphenyl substituted with from one to three substituents selected from thegroup consisting of fluorine, chlorine, bromine, iodine,trifluoromethyl, C₁ -C₃ acyloxy, -OSi(R₁)₃, C₁ -C₃ alkyl, C₁ -C₃ alkoxy,cyano, and nitro; ##STR5## in which Ar' is phenyl, pyridyl, orsubstituted phenyl as defined above, and Y is oxygen or sulfur; ##STR6##in which Ar is as defined above, and B is C₁ -C₃ acyloxy, ##STR7##esterified carboxyl, -CN, -N₃, or -NHR in which R is benzyloxycarbonyl,C₁ -C₄ alkoxycarbonyl, cycloalkoxycarbonyl, triphenylmethyl, ##STR8##2,2,2-trichloroethoxycarbonyl, or -Si(R₁)₃ in which R₁ is as hereindefined; (3-sydnone)C₂ -C₃ alkanoyl; ##STR9## in which R' is hydrogen ormethoxy; 2-(1H-tetrazol-1-yl)acetyl; and the like. Additional preferredamino protecting groups are those defined by R₃ and R₄ taken togetherwith the nitrogen atom to which they are bonded, and include, forexample, phthalimido, a cyclic imide moiety of a C₃ -C₁₂ dicarboxylicacid, 2,2-dimethyl-5-oxo-4-phenylimidazolidin-1-yl, or the like.

More preferred amino protecting groups include those in which R₃ ishydrogen and R₄ is ##STR10## in which Ar is phenyl, thienyl, or phenylsubstituted with from one to three substituents selected from the groupconsisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, C₁-C₃ acyloxy, -OSi(R₁)₃, C₁ -C₃ alkyl, C₁ -C₃ alkoxy, cyano, and nitro;##STR11## in which Ar' is phenyl, or substituted phenyl as definedabove, and Y is oxygen or sulfur; ##STR12## in which Ar is as definedabove, and B is C₁ -C₃ acyloxy, ##STR13## or -NHR in which R isbenzyloxycarbonyl, C₁ -C₄ alkoxycarbonyl, cycloalkoxycarbonyl,triphenylmethyl, ##STR14## 2,2,2-trichloroethoxycarbonyl, or -Si(R₁)₃ inwhich R₁ is as herein defined; ##STR15## in which R' is hydrogen ormethoxy; 2-(1H-tetrazol-1-yl)acetyl; or R₃ and R₄ taken together withthe nitrogen atom to which they are bonded are phthalimido or2,2-dimethyl-5-oxo-4-phenylimidazolidin-1-yl.

Especially preferred amino protecting groups include those in which R₃is hydrogen and R₄ is ##STR16## in which Ar is phenyl; ##STR17## inwhich Ar' is phenyl, and Y is oxygen; or R₃ and R₄ taken together withthe nitrogen atom to which they are bonded are2,2-dimethyl-5-oxo-4-phenylimidazolidin-1-yl.

The novel silyl esters described above are intermediates in theconversion of penicillin sulfoxides to desacetoxycephalosporins. As hasbeen developed in detail in Morin et al., Journal of the AmericanChemical Society, 91, (1969) pp. 1401-1407, ring expansion ofpenicillins to cephalosporins involves an oxidative cleavage of the C₂-sulfur bond producing a labile sulfenic acid intermediate having adouble bond at the C₂ carbon. This intermediate is subsequently ringclosed to achieve a 3-cephem cephalosporin. Due to the equilibriumcharacteristics of the reaction as it bears on the sulfenic acidintermediate, it is possible for the sulfenic acid to ring close to the3-cephem cephalosporin or to revert to the penicillin structure.Therefore, it is highly desirable to trap the sulfenic acid intermediatein the form of a stable derivative which can then be further reacted toachieve the desired cephalosporin product. It is precisely such aprocess which is defined as another aspect of this invention.

This invention relates to a process for converting a penicillinsulfoxide to a desacetoxycephalosporin by heating the penicillinsulfoxide in an inert, substantially anhydrous solvent to a temperatureof from about 75° C. to about 150° C. in the presence of a silylatingagent and simultaneously or subsequently treating the reaction mixturein an acidic medium.

The process of this invention is distinguishable from prior uses ofsilicon-containing compounds in conjunction with penicillin sulfoxides.Gutowski, Tetrahedron Letters, 21, (1970) pp. 1779-1782, describes theepimerization of penicillin sulfoxide esters when exposed to asilylating agent at room temperature for several days. Belgian Pat. No.763,104 teaches a process for reacting a penicillin sulfoxide by heatingthe sulfoxide to a temperature below 160° C. in an anhydrous medium andin the presence of a compound containing silicon and halogen and atleast one nitrogenous base present in a quantity of at least 5 moles permole of the sulfoxide.

In the process of this invention any silylating agent can be employedwhich will achieve the silylation of the sulfenic acid intermediateformed by thermal cleavage of the penicilin sulfoxide. Any suchsilylating agent will contain at least one moiety having the formula-Si(R₁)₃ in which R₁ is as herein defined, and, furthermore, such moietywill be so situated in the silylating agent molecule as to be readilycleavable therefrom under the conditions of reaction and therebyavailable for forming the azetidine-2-sulfenate silyl ester. Mixtures ofsilylating agents can likewise be employed. Preferably, any mixture ofsilylating agents will be such that each silylating agent will give riseto the same silyl protecting group. Preferred silylating agents includethose having the following formulae:

(a) ##STR18## in which each R₁ independently is C₁ -C₄ alkyl or phenyl,R'" is hydrogen, C₁ -C₄ alkyl, or phenyl, and X is ##STR19## in which Jis hydrogen or -Si(R₁)₃, or X is -CW₃ in which each W independently ishydrogen, trifluoromethyl, or C₁ -C₃ alkyl;

(b) ##STR20## in which R₁ and W are as herein defined; and (c) Z-Si(R₁)₃

in which R₁ is as herein defined and Z is halogen, C₂ -C₃ alkenyloxy, C₁-C₃ alkyl-SO₃ -, -O-Si(R₁)₃, -S-Si(R₁)₃, or ##STR21## in which R₅ ishydrogen or C₁ -C₃ alkyl, and R₆ is C₁ -C₄ alkyl or -Si(R₁)₃, or R₅ andR₆ taken together with the nitrogen atom to which they are bonded form aheterocyclic ring having 5 or 6 atoms, up to 3 of which, in addition tothe already-defined nitrogen atom, independently are nitrogen, sulfur,or oxygen.

Typical examples of the silylating agents which can be employed in theprocess of this invention include: N,O-bis(trimethylsilyl)acetamide,N,O-bis(triethylsilyl)acetamide, N,O-bis(triphenylsilyl)acetamide,N,O-bis(trimethylsilyl)trifluoroacetamide,N,O-bis(tripropylsilyl)trifluoroacetamide,N,O-bis(triphenylsilyl)trifluoroacetamide, N-trimethylsilylacetamide,N-tributylsilylacetamide, N-triphenylsilylacetamide,N-methyl-N-trimethylsilylacetamide, N-ethyl-N-triethylsilylacetamide,N-methyl-N-triphenylsilylacetamide, N-trimethylsilyl-N,N'-diphenylurea,N-triethylsilyl-N,N'-diphenylurea, N-triphenylsilyl-N,N'-diphenylurea,propenoxytrimethylsilane, ethenoxytriethylsilane,propenoxytriphenylsilane, trimethylsilyl methane sulfonate,tripropylsilyl ethane sulfonate, triphenylsilyl propane sulfonate,trimethylchlorosilane, triethylchlorosilane, triphenylchlorosilane,hexamethyldisilazane, hexaethyldisilazane, hexaphenyldisilazene,N-trimethylsilyl-t-butylamine, N-tripropylsilyl-t-butylamine,N-triphenylsilyl-t-butylamine, N-trimethylsilyldiethylamine,N-triethylsilyldimethylamine, N-triphenylsilylmethylethylamine,N-trimethylsilylimidazole, N-triethylsilylimidazole,a-triphenylsilylimidazole, hexamethyldisiloxane, hexapropyldisiloxane,hexaphenyldisiloxane, hexamethyldisilthiane, hexaethyldisilthiane,hexaphenyldisilthiane, and the like.

The conversion of the penicillin sulfoxide in accordance with theprocess of this invention is accomplished by heating the sulfoxide withthe chosen silylating agent to a temperature of from about 75° C. toabout 150° C. The heating of the sulfoxide is carried out in thepresence of an appropriate inert, substantially anhydrous solvent. Anysolvent can be employed which is inert to the penicillin sulfoxide andto the silylating agent and which has a sufficiently elevated boilingpoint to achieve the necessary reaction temperature. Suitable solventsinclude benzene, toluene, acetonitrile, dioxane, dimethylformamide,dimethylacetamide, and the like. Mixtures of appropriate solvents canalso be employed.

The reaction mixture containing the penicillin sulfoxide is heated inthe presence of a silylating agent at a temperature within the aboverange for a period necessary to effect conversion. This period can bevery short or somewhat longer depending upon the reactants which areemployed. Generally, the mixture will be heated for a period of fromabout 0.5 hours to about 24 hours. It is believed that the applicationof heat to the sulfoxide accomplishes a scission of the sulfur-C₂ bond.The scission of the sulfur-C₂ bond gives rise to a sulfenic acid typeintermediate which is susceptible to attack by the silylating agent. Theattack by the silylating agent traps the intermediate by production of astable silyl ester having the structure of the class of novelintermediates of this invention.

Since one silyl moiety is required for each sulfenic acid moiety, atleast an equimolar ratio of silylating agent to penicillin sulfoxidegenerally will be necessary. Certain silylating agents are so structuredas to generate two or more silyl moieties per molecular. Correspondinglylesser molar quantities of such silylating agents can be employed.Generally, an excess of from about 1.1 to about 4 equivalents of thesilylating agent will be employed per equivalent of the penicillinsulfoxide. Correspondingly, and as will be developed in detailhereinafter, certain penicillin sulfoxide starting materials will haveadditional points at which silylation can occur. In such instances oneadditional equivalent of the silyl moiety will be required for each suchpoint of silylation.

In preparing the silyl ester intermediate of this invention, any of theabove-mentioned silylating agents can be employed. However, stronglyalkaline conditions must be avoided, or cleavage of the β-lactam ringwill occur. Therefore, special precautions must be observed in thoseinstances in which a silazane is employed as silylating agent. Since theuse of a silazane results in the concomitant production of ammoniaduring silylation, care must be exercised to assure the immediateneutralization of the ammonia thus produced. This can be accomplished byincluding in the reaction mixture a minor amount of an acid whichinactivates the ammonia upon its generation. A like result can beachieved by employing a combination of the silazane and a halosilane assilylating agent. The halosilane will generate a hydrogen halide asby-product of the silyl ester formation, and the hydrogen halide, inturn, will scavenge the ammonia generated from the silazane.

Conversely, care must be exercised in employing a halosilane assilylating agent. Since a hydrogen halide is formed during suchsilylation, the acidic conditions thereby developed may cause ringclosure immediately to occur. In order to avoid this possibility, it ispreferred to employ a mixture of silylating agents containing asufficient amount of a silazane to neutralize by ammonia formation thehydrogen halide which forms.

The silyl ester intermediate either can be isolated from the silylationreaction mixture, or the silylation reaction mixture can be subjected toacid treatment to achieve ring closure of the silyl ester.Alternatively, the acid can be included with the penicillin sulfoxide inthe reaction mixture at the outset of the reaction. Under the latter setof reaction conditions, the silyl ester intermediate will be transient,and ring closure with decomposition of the silyl ester will occursubstantially simultaneously with the formation of the silyl ester.

Various acids can be employed in the ring closure portion of the processof this invention. Examples of suitable acids include sulfuric acid,phosphoric acid, and other mineral acids; methanesulfonic acid,p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid,and other sulfonic acids; boron trifluoride, ferric chloride, aluminumchloride, and other Lewis acids; and other commonly recognized acidicreagents.

Highly preferred acids are sulfonic acids. Examples of preferredsulfonic acids are the C₁ to C₁₂ -hydrocarbonsulfonic acids such as theC₁ to C₁₂ -alkanesulfonic acids such as methanesulfonic acid,ethanesulfonic acid, hexanesulfonic acids, nonanesulfonic acids,dodecanesulfonic acids, and the like, as well as the C₄ to C₇-cycloalkanesulfonic acids such as cyclobutanesulfonic acid,cyclopentanesulfonic acid, cyclohexanesulfonic acid, andcycloheptanesulfonic acid, the C₆ to C₁₂ aryl- and alkarylsulfonic acidssuch as benzenesulfonic acid, dodecylbenzenesulfonic acids, alpha- andbeta- naphthalenesulfonic acids, biphenylsulfonic acids,p-toluenesulfonic acid, xylenesulfonic acids, and the like, disulfonicacids such as methanedisulfonic acid, benzenedisulfonic acid, and thelike, benzenetrisulfonic acid, mixtures of sulfonic acids, and suchsulfonic acids substituted with groups that do not interfere with thering closure reaction, such as chlorine, bromine, nitro, cyano, and thelike, exemplified by p-chlorobenzenesulfonic acid,3,5-dibromobenzenesulfonic acid, 4-nitro-alpha-naphthalenesulfonic acid,and 4-cyanobenzenesulfonic acid. For economic reasons, the preferredsulfonic acids are C₁ to C₆ -alkanesulfonic acids such asmethanesulfonic acid, ethanesulfonic acid, and the simple C₆ to C₈ aryland alkaryl hydrocarbonsulfonic acids such as benzenesulfonic acid,p-toluenesulfonic acid, and the like.

The acidic substance can be employed in a wide range of proportionsrelative to the silyl ester intermediate. In general, the molar ratio ofthe silyl ester intermediate to the acidic substance will be from 1:1 toabout 100:1. Preferably, a molar ratio of the silyl ester intermediateto the acid ranges from about 5:1 to about 15:1. The concentration ofthe silyl ester intermediate in the total solvent system can varyextensively, but preferably the silyl ester intermediate constitutesfrom about 1 to about 20 percent by weight of the reaction mixture.

Preferably, the penicillin sulfoxide which is employed in the process ofthis invention is one having the formula ##STR22## in which R₃ ishydrogen and R₄ is hydrogen; C₁ -C₈ alkanoyl; azidoacetyl; cyanoacetyl;haloacetyl; ##STR23## in which Ar is phenyl, thienyl, furyl, pyrrolyl,or phenyl substituted with from one to three substituents selected fromthe group consisting of fluorine, chlorine, bromine, iodine,trifluoromethyl, C₁ -C₃ acyloxy, hydroxy, C₁ -C₃ alkyl, C₁ -C₃ alkoxy,cyano, and nitro; ##STR24## in which Ar' is phenyl, pyridyl, orsubstituted phenyl as defined above, and Y is oxygen or sulfur;##STR25## in which Ar is as defined above, and B is C₁ -C₃ acyloxy,hydroxyl, carboxyl, esterified carboxyl, -CN, -N₃, -NH₂, or -NHR inwhich R is benzyloxycarbonyl, C₁ -C₄ alkoxycarbonyl,cycloalkoxycarbonyl, triphenylmethyl, ##STR26## or2,2,2-trichloroethoxycarbonyl; (3-sydnone)C₂ -C₃ alkanoyl; ##STR27## inwhich R' is hydrogen or methoxy; 2-(1H-tetrazol-1-yl)acetyl; or R₃ andR₄ taken together with the nitrogen atom to which they are bonded arephthalimido, a cyclic imide moiety of a C₃ -C₁₂ dicarboxylic acid, or2,2-dimethyl-5-oxo-4-phenylimidazolidin-1-yl; and R₂ is hydrogen, C₁ -C₆alkyl, 2,2,2-trihaloethyl, 2-iodoethyl, benzyl, nitrobenzyl,tetrahydropyranyl, 9-fluorenyl, succinimidomethyl, phthalimidomethyl,methoxybenzyl, dimethoxybenzyl, cyanomethyl, nitrophenyl, dinitrophenyl,2,4,6-trinitrophenyl, bis(p-methoxyphenyl)methyl, triphenylmethyl,benzhydryl, benzyloxymethyl, C₂ -C₆ alkanoyloxymethyl, C₂ -C₄ alkanoyl,phenacyl, or a radical of the formula ##STR28## in which each R₁independently is C₁ -C₄ alkyl or phenyl.

The above definitions for R₂, R₃ and R₄ represent only a portion of thegroups now well recognized in the penicillin and cephalosporin arts.Penicillin sulfoxides containing any of these well known substituentscan be readily employed in the ring expansion process of this invention.

As mentioned above, it is contemplated by this invention to employ asstarting material the sulfoxide of 6-aminopenicillanic acid (6-APA):##STR29## When the above is employed, three points of silylation exist.In accordance with the process of this invention, the stable silylintermediate which will result during the thermal cleavage will have theformula ##STR30## Thus, inherent in the process of this invention is thegeneration from 6-APA of a silyl ester intermediate having both theamino and the carboxy moieties suitably protected. Under the acidicconditions at which ring closure is accomplished to produce thedesacetoxycephalosporin, both additional silyl protecting groups will becleaved to produce the highly desirable 7-aminodesacetoxycephalosporanicacid (7-ADCA). The process of this invention thus permits the directconversion of 6-APA sulfoxide to 7-ADCA. As will be apparent under theconditions of this specific conversion, it is essential that the ratioof silylating agent to 6-APA sulfoxide be such as will afford a minimumof three silyl moieties per each molecule of 6-APA sulfoxide.

It is correspondingly possible to employ as starting material apenicillin sulfoxide which has either a free amino function in the6-position or a free carboxy function in the 3-position. In suchinstances the ratio of silylating agent to penicillin sulfoxide will besuch as will afford a minimum of two silyl moieties per each molecule ofthe sulfoxide.

When R₃ of the sulfoxide starting material is hydrogen R₄ can behydrogen or a silyl protecting group, such as trimethylsilyl,triethylsilyl, and the like. When R₃ and R₄ are each hydrogen, theresulting silyl ester intermediate which is produced will have one ofthe hydrogens replaced by the silyl protecting group. When R₄ of thesulfoxide starting material is a silyl protecting group, such silylprotecting group will be retained in the silyl ester intermediate. Uponring-closure to form the desacetoxycephalosporin product, any silylgroup which would have been present at the 7-amino function will becleaved to produce a cephalosporin in which R₃ and R₄ are both hydrogen.

Representative of the silyl ester intermediates of this invention aswell as the penicillin sulfoxides which can be used in and thedesacetoxycephalosporins which can be prepared by the process of thisinvention are those in which R₂ is, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, amyl, hexyl,2,2,2-trichloroethyl, 2,2,2-tribromoethyl, 2-iodoethyl, benzyl,p-nitrobenzyl, tetrahydropyranyl, succinimidomethyl, phthalimidomethyl,p-methoxybenzyl, cyanomethyl, 3,4-dimethoxybenzyl, p-nitrophenyl,2,4-dinitrophenyl, 2,4,6-trinitrophenyl, bis(p-methoxyphenyl)methyl,triphenylmethyl, benzhydryl, benzyloxymethyl, acetoxymethyl,propionoxymethyl, acetyl, propionyl, phenacyl, and the like.

R₂ of the sulfoxide starting material can also be hydrogen or a silylprotecting group, such as trimethylsilyl, triethylsilyl, triphenylsilyl,and the like. When such a starting material is employed, the silyl esterintermediate which is produced will be appropriately silylated in itscarboxyl function. In the instance in which R₂ of the sulfoxide ishydrogen the carboxyl function of the silyl ester intermediate will beprotected with the silyl group of the silylating agent which has beenemployed. In the instance in which R₂ of the sulfoxide is itself a silylprotecting group, such group will be retained in the silyl esterintermediate. Upon treatment of this silyl ester intermediate with acidto produce ring-closure, the silyl group which protects the carboxylfunction can additionally be cleaved to produce the corresponding freeacid cephalosporin.

Of the above, those R₂ groups which are highly preferred includet-butyl, 2,2,2-trichloroethyl, p-nitrobenzyl, benzyl, p-methoxybenzyl,benzhydryl, and trimethylsilyl.

The amino group of the penicillin sulfoxides which are used in and thedesacetoxycephalosporins which are prepared by the process of thisinvention can incorporate any of a broad range of substituents.Representative examples of the R₄ substituent when R₃ is hydrogeninclude the following: formyl, acetyl, propionyl, butyryl, valeryl,caproyl, azidoacetyl, cyanoacetyl, chloroacetyl, bromoacetyl,phenylacetyl, 2-thienylacetyl, 3-thienylacetyl, 2-furylacetyl,3-furylacetyl, 2-pyrrolylacetyl, 3-pyrrolylacetyl, 4-chlorophenylacetyl,3-trifluoromethylphenylacetyl, 4-hydroxyphenylacetyl, 3-tolylacetyl,4-cumylacetyl, 4-methoxyphenylacetyl, 3-cyanophenylacetyl,4-nitrophenylacetyl, phenoxyacetyl, thiophenylacetyl, pyridyloxyacetyl,p-nitrophenoxyacetyl, α-aminophenylacetyl,α-benzyloxycarbamidophenylacetyl, α-t-butoxycarbamidophenylacetyl,α-formyloxyphenylacetyl, α-cyanophenylacetyl, α-azidophenylacetyl,3-sydnoneacetyl, 2-(1H-tetrazol-1-yl)acetyl, 2-nitrophenylthio,2-nitro-4-methoxyphenylthio, and the like. These as well as many othergroups are now well recognized in the art.

Of the above R₄ substituents, those which are higly preferred includephenylacetyl, 2-thienylacetyl, and phenoxyacetyl.

The silyl ester intermediates of this invention can likewise contain anyof the above substituents as well as many others, with the exception,however, that a reactive functional group which may be present in theR₂, R₃ or R₄ substituent of the penicillin sulfoxide may becomesilylated during formation of the intermediate. Upon ring closure of thethus-formed silyl ester intermediate to produce thedesacetoxycephalosporin, the addition silyl group will be cleaved togenerate a cephalosporin having the R₂, R₃ and R₄ substituents as theyexisted in the penicillin sulfoxide starting material. Illustrative ofthis is the situation in which R₃ is hydrogen and R₄ isα-aminophenylacetyl. In this instance the α-amino group would besilylated during formation of the silyl ester intermediate. Uponsubsequent ring closure this silyl group would be cleaved to regeneratein the thus-formed cephalosporin an α-aminophenylacetyl group at thenitrogen in the 7-position. In view of the above, the definitions of R₂and R₄ with respect to the penicillin sulfoxide and the silyl esterintermediate will in general correspond except in those instances inwhich the starting pencillin sulfoxide contains groups which can besilylated. As to such groups, R₂ and R₄ in the definition of the silylester intermediates is modified to account for the silylation effect.

When R₃ and R₄ are taken together with the nitrogen atom to which theyare bonded, representative examples of the combination include, forexample, phthalimido, succinimido,2,2-dimethyl-5-oxo-4-phenylimidazolidin-1-yl, and the like.

The prior art describes literally thousands of penicillin compoundswhich, by the process of this invention, can be converted todesacetoxycephalosporin compounds. Any of the penicillin sulfoxideswhich are employed as starting materials in the process of thisinvention are readily available by techniques known in the art. Forexample, pencillin G (benzylpenicillin) or penicillin V(phenoxymethylpenicillin) can be converted to their correspondingsulfoxides and these used as starting materials in the process of thisinvention. Both pencillin G and pencillin V are available eithernaturally or biosynthetically, and both can be readily cleaved toproduce 6-APA. 6-APA can itself be oxidized and thereby employed asstarting material in this invention. 6-APA also can be modified byacylation in the 6-position and/or estification in the 3-positionaccording to known techniques, thereby to produce any of the basicpenicillin structures, which, in turn, can be oxidized in accordancewith prior art techniques to produce the pencillin sulfoxides employedherein as starting materials.

Desacetoxycephalosporin compounds which are produced by the process ofthis invention from the corresponding penicillin sulfoxides, uponremoval of any carboxy and/or other protecting group which might bepresent, are useful as antibiotics in therapeutic treatment of diseasescaused by various Gram-positive and Gram-negative microorganisms.7-Aminodesacetoxycephalosporanic acid (7-ADCA), produced from 6-APAsulfoxide by the process of this invention, is additionally usful as anintermediate to prepare other desacetoxycephalosporin antibioticsubstances. Furthermore, any of the desacetoxycephalosporin products canbe cleaved to produce 7-ADCA. The thus-obtained 7-ADCA can then beacylated, for example, with 2-thiopheneacetyl chloride to obtain7-(2-thienyl)acetamido-3-methyl-3-cephem-4-carboxylic acid, a knownantibiotic.

Illustrative of the silyl ester intermediates of this invention are thefollowing:

Trimethylsilyl3-phthalimido-4-oxo-1-(1'-methoxycarbonyl-2'-methyl-2'-propenyl)azetidine-2-sulfenate.

Trimethylsilyl3-phthalimido-4-oxo-1-(1'-trimethylsilyloxycarbonyl-2'-methyl-2'-propenyl)azetidine-2-sulfenate.

Trimethylsilyl3-phenoxyacetamido-4-oxo-1-(1'-p-nitrobenzyloxycarbonyl-2'-methyl-2'-propenyl)azetidine-2-sulfenate.

Triethylsilyl3-phenylacetamido-4-oxo-1-[1'-(2,2,2-trichloroethoxycarbonyl)-2'-methyl-2'-propenyl]azetidine-2-sulfenate.

Trimethylsilyl3-trimethylsilylamino-4-oxo-1-(1'-trimethylsilyloxycarbonyl-2'-methyl-2'-propenyl)azetidine-2-sulfenate.

Trimethylsilyl3-(α-trimethylsilylaminophenylacetamido)-4-oxo-1-(1'-p-nitrobenzyloxycarbonyl-2'-methyl-2'-propenyl)azetidine-2-sulfenate.

Trimethylsilyl3-(2'-thienyl)acetamido-4-oxo-1-(1'-benzyhydryloxycarbonyl-2'-methyl-2'-propenyl)azetidine-2-sulfenate.

Tributylsilyl3-(4'-hydroxyphenyl)acetamido-4-oxo-1-(1'-benzyloxycarbonyl-2'-methyl-2'-propenyl)azetidine-2-sulfenate.

Triphenylsilyl3-succinimido-4-oxo-1-[1'-(2-iodo)-ethyloxycarbonyl-2'-methyl-2'-propenyl]azetidine-2-sulfenate.

Trimethylsilyl3-(3'-sydnone)acetamido-4-oxo-1-(1'-t-butoxycarbonyl-2'-methyl-2'-propenyl)azetidine-2-sulfenate.

Trimethylsilyl3-(α-trimethylsilyloxyphenylacetamido)-4-oxo-1-(1'-p-hydroxybenzyloxycarbonyl-2'-methyl-2'-propenyl)azetidine-2-sulfenate.

Trimethylsilyl3-(2',2'-dimethyl-3'-trimethylsilyl-5'-oxo-4'-phenylimidazolidin-1'-yl)-4-oxo-1-(1'-triphenylsilyloxycarbonyl-2'-methyl-2'-propenyl)azetidine-2-sulfenate.

Trimethylsilyl3-(2'-furyl)acetamido-4-oxo-1-[1'-(9-fluorenyloxycarbonyl)-2'-methyl-2'-propenyl]azetidine-2-sulfenate.

Triethylsilyl3-(4'-chlorophenyl)acetamido-4-oxo-1-(1'-p-methoxybenzyloxycarbonyl-2'-methyl-2'-propenyl)azetidine-2-sulfenate.

Trimethylsilyl3-formamido-4-oxo-1-(1'-phthalimidomethoxycarbonyl-2'-methyl-2'-propenyl)azetidine-2-sulfenate.

Tripropylsilyl3-(α-benzyloxycarbamido)phenylacetyl-4-oxo-1-(1'-p-methoxybenzyloxycarbonyl-2'-methyl-2'-propenyl)azetidine-2-sulfonate.

Trimethylsilyl3-(3'-tolyl)acetamido-4-oxo-(1'-tetrahydropyranyloxycarbonyl-2'-methyl-2'-propenyl)azetidine-2-sulfenate.

Trimethylsilyl3-thiophenoxyacetamido-4-oxo-1-(1'-benzhydryloxycarbonyl-2'-methyl-2'-propenyl)azetidine-2-sulfenate.

Trimethylsilyl3-(2'-pyrrolyl)acetamido-4-oxo-1-(1'-ethoxycarbonyl-2'-methyl-2'-propenyl)azetidine-2-sulfenate.

Trimethylsilyl3-(3'-thienyl)acetamido-4-oxo-1-(1'-benzyloxycarbonyl-2'-methyl-2'-propenyl)azetidine-2-sulfenate.

Trimethylsilyl3-[2'-(1H-tetrazol-1-yl)acetamido]-4-oxo-1-(1'-p-nitrobenzyloxycarbonyl-2'-methyl-2'-propenyl)-azetidine-2-sulfenate.

Typical conversions of penicillin sulfoxides to desacetoxycephalosporinsin accordance with the process of this invention include the following:

p-Nitrobenzyl 6-phenoxyacetamido-2,2-dimethylpenam-1-oxide-3-carboxylateto obtain p-nitrobenzyl7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate.

t-Butyl 6-(2-thienyl)acetamido-2,2-dimethylpenam-1-oxide-3-carboxylateto obtain t-butyl7-(2-thienyl)-acetamido-3-methyl-3-cephem-4-carboxylate.

2,2,2-Trichloroethyl6-α-aminophenylacetamido-2,2-dimethylpenam-1-oxide-3-carboxylate toobtain 2,2,2-trichloroethyl7-α-aminophenylacetamido-3-methyl-3-cephem-4-carboxylate.

p-Nitrobenzyl6-(2',2'-dimethyl-5'-oxo-4'-phenylimidazolidin-1'-yl)-2,2-dimethylpenam-1-oxide-3-carboxylateto obtain p-nitrobenzyl7-(2',2'-dimethyl-5'-oxo-4'-phenylimidazolidin-1'-yl)-3-methyl-3-cephem-4-carboxylate.

Benzhydryl6-(α-formyloxy)phenylacetamido-2,2-dimethylpenam-1-oxide-3-carboxylateto obtain benzhydryl7-(α-formyloxy)phenylacetamido-3-methyl-3-cephem-4-carboxylate.

Benzyl 6-(3-sydnone)acetamido-2,2-dimethylpenam-1-oxide-3-carboxylate toobtain benzyl 7-(3-sydnone)acetamido-3-methyl-3-cephem-4-carboxylate.

2-Iodomethyl6-[2-(1H-tetrazol-1-yl]acetamido-2,2-dimethylpenam-1-oxide-3-carboxylateto obtain 2-iodomethyl7-[2-(1H-tetrazol-1-yl)]acetamido-3-methyl-3-cephem-4-carboxylate.

6-Amino-2,2-dimethylpenam-1-oxide-3-carboxylic acid to obtain7-amino-3-methyl-3-cephem-4-carboxylic acid.

Triphenylmethyl 6-succinimido-2,2-dimethylpenam-1-oxide-3-carboxylate toobtain triphenylmethyl 7-succinimido-3-methyl-3-cephem-4-carboxylate.

Trimethylsilyl6-thiophenoxyacetamido-2,2-dimethylpenam-1-oxide-3-carboxylate to obtain7-thiophenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid.

Methyl 6-(2-furyl)acetamido-2,2-dimethylpenam-1-oxide-3-carboxylate toobtain methyl 7-(2-furyl)acetamido-3-methyl-3-cephem-4-carboxylate.

p-Nitrobenzyl6-(N-trimethylsilyl)amino-2,2-dimethylpenam-1-oxide-3-carboxylate toobtain p-nitrobenzyl 7-amino-3-methyl-3-cephem-4-carboxylate.

Benzhydryl 6-phenylacetamido-2,2-dimethylpenam-1-oxide-3-carboxylate toobtain benzhydryl 7-phenylacetamido-3-methyl-3-cephem-4-carboxylate.

Benzyl6-(2-nitrophenyl)sulfenamide-2,2-dimethylpenam-1-oxide-3-carboxylate toobtain benzyl7-(2-nitrophenyl)sulfenamide-3-methyl-3-cephem-4-carboxylate.

p-Nitrobenzyl6-(2-nitro-4-methoxyphenyl)sulfenamide-2,2-dimethylpenam-1-oxide-3-carboxylateto obtain p-nitrobenzyl7-(2-nitro-4-methoxyphenyl)sulfenamide-3-methyl-3-cephem-4-carboxylate.

This invention is further illustrated by the following detailedexamples.

EXAMPLE 1

Into a 50 ml., 3-neck flask was placed 752 mg. (2 millimoles) of methyl6-phthalimido-2,2-dimethylpenam-1-oxide-3-carboxylate. To the flask werethen added 10 ml. of benzene, 0.26 ml. (2 millimoles) oftrimethylchlorosilane, and 0.21 ml. (1 millimole) ofhexamethyldisilazane. The resulting mixture was stirred and refluxed forabout 16 hours at 78°-80° C. The reaction mixture was then evaporated invacuo to produce a residue of approximately a quantitative yield oftrimethylsilyl3-phthalimido-4-oxo-1-(1'-methoxycarbonyl-2'-methyl-2'-propenyl)azetidine-2-sulfenate.

Analysis, Calc. for C₂₀ H₂₄ N₂ O₆ Si: C, 53.57; H, 5.39; N, 6.25: Found:C, 53.76; H, 5.55; N, 6.42.

[δ]_(d) ²⁷ -164.4° (benzene) UV_(max) 220 mμ (ξ=47,200) 291 mμ(ξ=10,500) IR 2990, 2920, 1770, 1735, 1715, 1390, 1245, 874, 845 and 705cm⁻¹.

Nmr (δ) 0.05 (s, 9H), 2.04 (s, 3H), 3.84 (s, 3H), 5.07 (two overlappings), 5.20 (6s, 1H), 5.84 (s, AB, 2H), 7.86 (m, 4H).

Ms m/e 448, 433, 359, 327, 299, 293, 262, 239, 204, 187, 172, 160, 113,104, 89, 73.

EXAMPLE 2

To a suspension of 376 mg. of methyl6-phthalimido-2,2-dimethylpenan-1-oxide-3-carboxylate in 10 ml. ofbenzene was added 0.25 ml. of N,O-bis(trimethylsilyl)acetamide. Theresulting mixture was heated to reflux (about 78° C.) for about 22hours. The reaction mixture was cooled to room temperature andevaporated in vacuo to produce a brown gum which exhibited an NMRspectrum consistent for the expected trimethylsilyl ester intermediate.

EXAMPLE 3

To a 50 ml., 3-neck flask was added 752 mg. (2 millimoles) of methyl6-phthalimido-2,2-dimethylpenam-1-oxide-3-carboxylate in 10 ml. ofbenzene. To the resulting mixture was added 0.26 ml. (2 millimoles) oftrimethylchlorosilane and 0.21 ml. (1 millimole) ofhexamethyldisilazane. The resulting mixture was refluxed overnight afterwhich the mixture was cooled to room temperature and evaporated in vacuoto produce a clear very viscous liquid. IR analysis established thepresence of a β-lactam ring. MS analysis indicated the following m/evalues: 448, 433, 389, 327, 359, 299, 293, 262, 239, 294, 204, 187, 172,160, 152, 130, 120, 113, 104, 89 and 73. NMR analysis was consistent forthe expected trimethylsilyl ester intermediate.

A sample of the above trimethylsilyl ester intermediate was treated withone equivalent of methanesulfonic acid in a 1:1 volume mixture ofbenzene and dimethylacetamide. The mixture was permitted to stand atroom temperature overnight. The reaction mixture was then evaporated todryness in vacuo at about 55° C. The residue was dissolved in a smallamount of benzene and placed on a 1.5×21 cm. silica gel column. Thesample was eluted from the column using 100 ml. quantities of benzene,5% ethyl acetate in benzene, 10% ethyl acetate in benzene, and 15% ethylacetate in benzene. Fractions of 20 ml. each were collected. Methyl7-phthalimido-3-methyl-3-cephem-4-carboxylate in a yield of about 50%was obtained from fractions 7, 8, 9, and 10.

Analysis: NMR (CDCl₃) (δ) 2.34 (s, 3H), 3.39 (d, J=16 and 47, 2H), 3.85(s, 3H), 5.12 (d, J=4.5, 1H), 5.42 (d, J=4.5, 1H), and 7.82 (m, 4H).

IR (CHCl₃) 3020, 2970, 1800, 1785, 1725, 1390, 1220, 1110, and 907 cm⁻¹.

EXAMPLE 4

A mixture of 752 mg. (2 millimoles) of methyl6-phthalimido-2,2-dimethylpenam-1-oxide-3-carboxylate, (393 mg. (3millimoles) of N-trimethylsilylacetamide, and 10 ml. of benzene wasrefluxed (78° C.) for about 16 hours. The reaction mixture was thencooled to room temperature and evaporated in vacuo to a glassy solidresidue. NMR of the residue was consistent for the trimethylsilyl esterintermediate.

The residue was re-dissolved in 10 ml. of benzene, and 20 mg. (0.2millimole) of methanesulfonic acid dissolved in 2 ml. of a 60:40 mixtureof dimethylacetamide and benzene was added. The resulting mixture wasstirred at room temperature for about 16 hours. Thin-layerchromatography (TLC) of the reaction mixture showed the presence of amajor amount (estimated greater than 70%) of methyl7-phthalimido-3-methyl-3-cephem-4-carboxylate.

EXAMPLE 5

Into a 50 ml. 3-neck flask were placed 994 mg. (2 millimoles) ofp-nitrobenzyl 6-phthalimido-2,2-dimethylpenam-1-oxide-3-carboxylate, 10ml. of benzene, 0.26 ml. (2 millimoles) of trimethylchlorosilane, and0.21 ml. (1 millimole) of hexamethyldisilazane. The mixture was heatedto reflux (78°-80° C.) with stirring for about 16 hours. A small amountof solid formed in the reaction mixture and was filtered off. Thefiltrate was evaporated to dryness in vacuo to recover a yellow gumwhich by IR and NMR analysis was shown to be trimethylsilyl3-phthalimido-4-oxo-1-(1'-p-nitrobenzyloxycarbonyl-2'-methyl-2'-propenyl)azetidine-2-sulfenate.

Nmr (cdcl₃) (δ) 0.05 (s, 9H), 2.09 (s, 3H), 5.14 (s, 1H), 5.33 (twooverlapping s, 2H), 5.37 (s, 2H), 5.97 (s, 2H), 7.86 (s, 4H), 7.91 (q,4H, J=90 and 40).

Ir (chcl₃) 3050, 2960, 1840, 1785, 1725, 1640, 1500, 1100, and 846 cm⁻¹.

EXAMPLE 6

To 50 ml. of benzene were added 1.75 grams (5 millimoles)6-phthalimido-2,2-dimethylpenam-1-oxide-3-carboxylic acid, 1.3 ml. (10millimoles) of trimethylchlorosilane, and 1.05 ml. (5 millimoles) ofhexamethyldisilazane. The mixture was refluxed (78°-80° C.) for about4.5 hours. The reaction mixture was then cooled to room temperature andevaporated in vacuo to produce a residue of trimethylsilyl3-phthalimido-4-oxo-1-(1'-trimethylsilyloxycarbonyl-2'-methyl-2'-propenyl)azetidine-2-sulfenatein approximately quantitative yield.

Analysis, Calc.: for C₂₂ H₃₀ N₂ O₆ Si₂ ; C, 52.15; H, 5.97; N, 5.53; S,6.32; Found: C, 51.98; H, 5.85; N, 5.58; S, 6.18.

[δ]_(d) ²⁷ -45.5° (benzene)

Ir (cdcl₃) 3010, 2960, 1795, 1775, 1740, 1725, 1382, 1250, 1063, 844,and 707 cm⁻¹.

Nmr (cdcl₃) (δ) 0.05 (s, 9H), 0.37 (s, 9H), 2.05 (s, 3H), 5.01 (s, 1H),5.12 (s, 1H), 5.20 (s, 1H), 5.84 (s, AB pattern, 2H), and 7.84 (m, 4H).

Ms m/e 506, 491, 416, 401, 388, 300, 299, 232, 230, 204, 187, 160, 147,132, 114, 104, 73.

EXAMPLE 7

To a 250 ml., 3-neck flask were added 50 ml. of benzene, 2.6 grams(about 20 millimoles) of N-trimethylsilylacetamide, and 1.75 grams (5millimoles) of 6-phthalimido-2,2-dimethylpenam-1-oxide-3carboxylic acid.The mixture was stirred for about 5 minutes, after which solution wasabout complete. The mixture was then heated slowly to reflux (about 80°C.) and maintained thereat for about 5 hours. The mixture was thencooled to room temperature, during which time a minor amount of solidcrystallized out. The solid was filtered, and the filtrate wasevaporated to dryness in vacuo to produce a residue confirmed by NMRanalysis to be trimethylsilyl3-phthalimido-4-oxo-1-(1'-trimethylsilyloxycarbonyl-2'-methyl-2'-propenyl)azetidine-2-sulfenate.

EXAMPLE 8

To a solution of 380 mg. (1 millimole) of methyl6-phenoxyacetamido-2,2-dimethylpenam-1-oxide-3-carboxylate in 15 ml. ofdry toluene maintained at 40° C. were added 330 mg. (about 2 millimoles)of N-trimethylsilylacetamide and 0.023 ml. (about 0.2 millimole) oftrimethylchlorosilane. The resulting mixture was refluxed at about 111°C. for about 5 hours. The reaction mixture was then cooled to roomtemperature and evaporated in vacuo to a brown gummy solid residue. NMRanalysis established that the residue contained trimethylsilyl3-phenoxyacetamido-4-oxo-1-(1'-methoxycarbonyl-2'-methyl-2'-propenyl)-azetidine-2-sulfenate.

Nmr (cdcl₃) 0.05 (s, 9H), 2.04 (s, 3H), 3.75 (s, 3H), 4.54 (s, 2H), 5.07(s, 2H), 5.47 (s, 1H), 5.67 (q, J=4.5 and 8.0, 1H), 6.17 (d, J=4.5, 1H),7.85 (d, J=8.0, 1H).

EXAMPLE 9

To a solvent mixture of 25 ml. of 60% toluene and 40% acetonitrile wereadded 1.25 grams (2.5 millimoles) of p-nitrobenzyl6-phenoxyacetamido-2,2-dimethylpenam-1-oxide-3-carboxylate, 1.0 gram(7.5 millimoles) of N-trimethylsilylacetamide, and 0.19 ml. (1.5millimoles) of trimethylchlorosilane. The mixture was heated to reflux(about 87° C.) and maintained thereat for about 20 hours. The mixturewas then cooled to room temperature, and about 0.17 ml. ofmethanesulfonic acid was added. The mixture was then stirred at roomtemperature for about 16 hours. A minor amount of solid formed in themixture. The solid was removed by filtration, and the filtrate was shownby thin-layer chromatography (TLC) to contain principally p-nitrobenzyl7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate.

EXAMPLE 10

To a mixture of 25 ml. of benzene and 18 ml. of dimethylacetamide wereadded 2.5 grams (5 millimoles) of p-nitrobenzyl6-phenoxyacetamido-2,2-dimethylpenam-1-oxide-3-carboxylate, 2 grams(about 15 millimoles) of N-trimethylsilylacetamide, and 0.19 ml. (1.5millimoles) of trimethylchlorosilane. The resulting mixture was heatedto reflux (91° C.). The mixture was refluxed for about 20 hours, afterwhich time it was cooled to room temperature and 0.11 ml. ofmethanesulfonic acid was added. The mixture was then stirred at roomtemperature for about 16 hours. The reaction mixture was then evaporatedin vacuo to a residue. The residue was dissolved in 20 ml. of benzene. Aminor amount of insoluble crystalline material remained which wasfiltered off. The filtrate was then passed onto a silica gelchromatographic column, and the sample eluted therefrom usingsuccessively 200 ml. of 5% ethyl acetate in benzene, 1000 ml. of 10%ethyl acetate in benzene, and 400 ml. of 15% ethyl acetate in benzene torecover p-nitrobenzyl7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate.

EXAMPLE 11

Into a 250 ml. 3-neck flask were placed 25 ml. of dimethylacetamide,62.5 ml. of dry toluene, 1.84 grams (14 millimoles) ofN-trimethylsilylacetamide, and 0.091 ml. (1.4 millimoles) ofmethanesulfonic acid. To the resulting mixture was added 5.0 grams (10millimoles) of p-nitrobenzyl6-phenoxyacetamido-2,2-dimethylpenam-1-oxide-3-carboxylate. The mixturewas refluxed (115° C.) for about 1.5 hours, after which the resultingdark red solution was evaporated in vacuo to a residue of about 10grams. The residue was cooled and seeded with a small amount ofp-nitrobenzyl 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate, afterwhich crystallization began. Ethanol (50 ml.) was slowly added tocomplete crystallization of the product. The solid was filtered, washedwith ethanol, and vacuum-dried to yield 2.6 grams of p-nitrobenzyl7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate.

EXAMPLE 12

To a mixture of 25 ml. of dimethylacetamide and 62 ml. of dry toluenewere added 1.31 grams (10 millimoles) of N-trimethhylsilylacetamide and5.0 grams (10 millimoles) of p-nitrobenzyl6-phenoxyacetamido-2,2-dimethylpenam-1-oxide-3-carboxylate. The mixturewas refluxed at 118° C. for about 0.5 hour, after which the resultinglight brown solution was cooled to about 80° C. and 0.065 ml. (1millimole) of methanesulfonic acid was added. The mixture was thenrefluxed at 118° C. for an additional one hour. The brown solution wasevaporated in vacuo to a residue of about 10 grams. The residue wascooled and seeded, after which crystallization began to occur. About 50ml. of ethanol was slowly added, and the resulting mixture was filtered.The solid was washed with additional ethanol and vacuum-dried overnightat 40° C. to yield 2.0 grams of p-nitrobenzyl7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate.

EXAMPLE 13

To a mixture of 50 ml. of benzene and 37.5 ml. of dimethylacetamide wasadded 5.0 grams (10 millimoles) of p-nitrobenzyl6-phenoxyacetamido-2,2-dimethylpenam-1-oxide-3-carboxylate. To theresulting solution were then added 1.26 ml. (10 millimoles) oftrimethylchlorosilane and 1.05 ml. (5 millimoles) ofhexamethyldisilazine. The mixture was refluxed at 95° C. for 14.5 hours,and the resulting dark red mixture was then cooled to room temperature.To the mixture was then added 0.058 ml. (0.9 millimole) ofmethanesulfonic acid. The mixture was stirred for 15 minutes at about30° C. and then stirred for about 100 minutes at 55° C. The reactionmixture was then evaporated to near dryness and 10 ml. of ethanol wasadded. Crystals began to form after about one hour, at which time anadditional 30 ml. of ethanol was added. The mixture was refrigerated forthree days, and the crystals were filtered. The crystals werere-dissolved in 5 ml. of dioxane to which was then added 15 ml. ofethanol. Crystals began slowly to form. The crystals were filtered,washed with ethanol and dried to yield 550 mg. of p-nitrobenzyl7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate.

EXAMPLE 14

A mixture of 5.0 grams (10 millimoles) of p-nitrobenzyl6-phenoxyacetamido-2,2-dimethylpenam-1-oxide-3-carboxylate in 60 ml. ofdioxane was prepared and warmed to about 40° C. To this warmed mixturewere added 1.26 ml. (10 millimoles) of hexamethyldisilazane. Theresulting mixture was heated slowly to a temperature of 100° C. andmaintained thereat for about 5 hours during which time it turned from alight yellow solution fo a light brown solution.

The mixture was then cooled to about 40° C. and 0.04 ml. of borontrifluoride etherate was added. The solution turned slightly red andstirring at room temperature was continued for about 16 hours. Thereaction mixture was then evaporated to near dryness in a rotaryevaporator. The residue was recrystallized from 20 ml. of a 1:3 mixtureof dioxane and ethanol containing about 1 ml. of dimethylacetamide toproduce p-nitrobenzyl 7-phenoxyacetamido-3-methyl-3-cephem-carboxylate.

EXAMPLE 15

To a mixture of 25 ml. of benzene and 19 ml. of dimethylacetamide wereadded 2.45 grams (5 millimoles) of 2,2,2-trichloroethyl6-phenoxyacetamido-2,2-dimethylpenam-1-oxide-3-carboxylate, 1.7 grams(about 10 millimoles) of N-trimethylsilylacetamide and 0.035 ml. (0.5millimole) of methanesulfonic acid. The mixture was refluxed at 95°-96°C. for 15.5 hours. The reaction mixture was then extracted three timeswith water, and the benzene layer was dried over magnesium sulfate. NMRand TLC analyses established the structure of the product present in thebenzene layer to be 2,2,2-trichloroethyl7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate.

Nmr (cdcl₃) (δ) 2.20 (s, 3H), 3.20 and 3.57 (2d, 2H), 4.55 (s, 2H), 4.87(d, 2H), 5.03 (d, J=4.5, 1H), 5.83 (d, J=4.5 and 8.0, 1H), 6.80-7.40 (m,5H), 7.94 (d, J=8.0, 1H).

EXAMPLE 16

A solution of 1.41 grams (3 millimoles) of p-nitrobenzyl6-phenylacetamido-2,2-dimethylpenam-1-oxide-3-carboxylate in 30 ml. ofdioxane was prepared. To the resulting solution were added 17 ml. of drybenzene followed by 730 mg. (4.5 millimoles) ofN-trimethylsilylacetamide and 0.06 ml. of trimethylchlorosilane. Theresulting mixture was refluxed at 84° C. for 16 hours. The reactionmixture, a light yellow, clear solution, was cooled to about 50° C., and0.002 ml. of methanesulfonic acid was added. The mixture was thenmaintained at about 50° C., stirred for two hours, and then evaporatedto dryness in vacuo. The residue, unable to be recrystallized fromethanol, remained in the form of a gum which, by TLC analysis, was shownto contain p-nitrobenzyl7-phenylacetamido-3-methyl-3-cephem-4-carboxylate.

EXAMPLE 17

To 20 ml. of dioxane was added 700 mg. (3 millimoles) of6-aminopenicillanic acid sulfoxide, and the resulting mixture was warmedto about 60° C. A tiny drop of trifluoroacetic acid was added followedby 1.3 grams (about 10 millimoles) of N-trimethylsilylacetamide, thetrifluoroacetic acid being added to neutralize a trace of triethylamineimpurity present in the N-trimethylsilylacetamide. The mixture washeated to reflux for about 3 hours, during which time the mixture turnedto a red-brown color but remained clear. The mixture was then evaporatedto dryness in vacuo to produce a red-brown gum.

The gum was dissolved in 20 ml. of dry benzene, and 0.02 ml. ofmethanesulfonic acid was added and the mixture stirred at 50° C. for 2.5hours. The mixture was cooled to room temperature and 10 ml. of methanolwas added dropwise followed by 5.0 ml. of water. A solid precipitatedfrom the mixture, and the mixture was stirred for about 20 minutes,filtered, and the filtrate was evaporated under vacuum. The residue wasthen suspended in water, and aqueous sodium bicarbonate solution wasadded to pH 8.0. The solid dissolved at this pH, and the pH was thenadjusted to 3.5 by addition of acid, and a precipitate formed. Theprecipitate was filtered, and dried in vacuo to give 40 mg. of amaterial established by TLC, IR, and UV to be7-amino-3-methyl-3-cephem-4-carboxylic acid.

Ir (mull) 2960, 2870, 1800, 1620, 1530, 1350, 795, and 786 cm⁻¹.

Uv_(max) (pH 6.8 buffer) 262 mμ (ξ=72,200) 245 mμ (ξ=62,500).

EXAMPLE 18

To about 100 ml. of toluene were added 3.82 grams of6-phenoxyacetamido-2,2-dimethylpenam-1-oxide-3-carboxylic acid, about 4grams of N-trimethylsilylacetamide, and 0.07 ml. of methanesulfonicacid. The mixture was refluxed at 111° C. for about 16 hours. To thetarry dark brown reaction mixture 30 ml. of methanol was added. A TLC ofthe reaction mixture indicated the presence of7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid. The reactionmixture was evaporated to dryness in vacuo, and 25 ml. of acetonitrilewas added to the residue. Insolubles were filtered off, and the filtratewas evaporated in vacuo. About 25 ml. of ethyl acetate was added to theresidue. The ethyl acetate solution was extracted with 25 ml. ofsaturated aqueous sodium bicarbonate. The aqueous layer was thenseparated, washed with 25 ml. of ethyl acetate, separated, and slurriedwith an additional 25 ml. of ethyl acetate. The pH of the resultingmixture was adjusted to about 3.3 by addition of concentrated HCl. Theaqueous layer was separated from the ethyl acetate layer, and the ethylacetate layer was washed with 25 ml. of water. The ethyl acetate wasthen extracted with 25 ml. of saturated aqueous sodium bicarbonate. Theaqueous sodium bicarbonate was washed twice with 25 ml. of ethyl acetateand then slurried with an additional 25 ml. of ethyl acetate and the pHadjusted to about 2.5 by addition of concentrated HCl. The ethyl acetatelayer was separated and washed with 25 ml. of water. Activated charcoaland MgSO₄ was added to the ethyl acetate layer; the mixture was stirredfor about 30 minutes and filtered. The filtrate was evaporated to about20 ml., seeded, and refrigerated to produce crystalline7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid.

I claim:
 1. A compound of the formula ##STR31## in which each R₁ independently is C₁ -C₄ alkyl or phenyl; R₂ is C₁ -C₆ alkyl, 2,2,2-trihaloethyl, 2-iodoethyl, benzyl, nitrobenzyl, tetrahydropyranyl, 9-fluorenyl, succinimidomethyl, phthalimidomethyl, methoxybenzyl, dimethoxybenzyl, cyanomethyl, nitrophenyl, dinitrophenyl, 2,4,6-trinitrophenyl, bis(p-methoxyphenyl)methyl, triphenylmethyl, benzhydryl, benzyloxymethyl, C₂ -C₆ alkanoyloxymethyl, C₂ -C₄ alkanoyl, phenacyl, or a radical of the formula ##STR32## in which each R₁ is as herein defined; R₃ is hydrogen and R₄ is C₁ -C₈ alkanoyl; azidoacetyl; cyanoacetyl; haloacetyl; ##STR33## in which Ar is phenyl, thienyl, furyl, pyrrolyl, or phenyl substituted with from one to three substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, C₁ -C₃ acyloxy, -OSi(R₁)₃ in which R₁ is as herein defined, C₁ -C₃ alkyl, C₁ -C₃ alkoxy, cyano, and nitro; ##STR34## in which Ar' is phenyl, pyridyl, or substituted phenyl as defined above, and Y is oxygen or sulfur; ##STR35## in which Ar is as defined above, and B is C₁ -C₃ acyloxy, ##STR36## esterified carboxyl, -CN, -N₃, or -NMR in which R is benzyloxycarbonyl, C₁ -C₄ alkoxycarbonyl, cycloalkoxycarbonyl, triphenylmethyl, ##STR37##
 2. 2,2-trichloroethoxycarbonyl, or -Si(R₁)₃ in which R₁ is as herein defined; (3-sydnone) C₂ -C₃ alkanoyl; ##STR38## in which R' is hydrogen or methoxy; 2-(1H-tetrazol-1-yl)acetyl; or R₃ and R₄ taken together with the nitrogen atom to which they are bonded are phthalimido, a cyclic imide moiety of a C₃ -C₁₂ dicarboxylic acid, or 2,2-dimethyl-5-oxo-4-phenylimidazolidin-1-yl.
 2. Compound of claim 1, in which R₁ is methyl or phenyl; R₂ is C₁ -C₆ alkyl, 2,2,2-trihaloethyl, benzyl, nitrobenzyl, methoxybenzyl, benzhydryl, C₂ -C₆ alkanoyloxymethyl, phenacyl, or a radical of the formula ##STR39## in which R₁ is methyl or phenyl; R₃ is hydrogen and R₄ is ##STR40## in which Ar is phenyl, thienyl, or phenyl substituted with from one to three substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, C₁ -C₃ acyloxy, -OSi(R₁)₃, C₁ -C₃ alkyl, C₁ -C₃ alkoxy, cyano, and nitro; ##STR41## in which Ar' is phenyl, or substituted phenyl as defined above, and Y is oxygen or sulfur; ##STR42## in which Ar is as defined above, and B is C₁ -C₃ acyloxy, ##STR43## or -NHR in which R is benzyloxycarbonyl, C₁ -C₄ alkoxycarbonyl, cycloalkoxycarbonyl, triphenylmethyl, ##STR44##
 2. 2,2-trichloroethoxycarbonyl, or -Si(R₁)₃ in which R₁ is as herein defined; ##STR45## in which R' is hydrogen or methoxy; 2-(1H-tetrazol-1-yl)acetyl; or R₃ and R₄ taken together with the nitrogen atom to which they are bonded are phthalimido or 2,2-dimethyl-5-oxo-4-phenylimidazolidin-1-yl.
 3. Compound of claim 1, in which R₁ is methyl; R₂ is C₁ -C₆ alkyl, 2,2,2-trihaloethyl, benzyl, nitrobenzyl, methoxybenzyl, benzhydryl, phenacyl, or a radical of the formula (CH₃)₃ Si-; R₃ is hydrogen and R₄ is ##STR46## in which Ar is phenyl; ##STR47## in which Ar' is phenyl, and Y is oxygen; or R₃ and R₄ taken together with the nitrogen atom to which they are bonded are 2,2-dimethyl-5-oxo-4-phenylimidazolidin-1-yl.
 4. Compound of claim 1, in which R₁ is methyl.
 5. Compound of claim 1, in which R₂ is t-butyl, 2,2,2-trichloroethyl, p-nitrobenzyl, benzyl, p-methoxybenzyl, benzhydryl, or trimethylsilyl.
 6. Compound of claim 1, in which R₃ is hydrogen and R₄ is ##STR48## in which Ar is phenyl.
 7. Compound of claim 1, in which R₃ is hydrogen and R₄ is ##STR49## in which Ar' is phenyl and Y is oxygen.
 8. Compound of claim 1, in which R₃ is hydrogen and R₄ is ##STR50## in which Ar is 2-thienyl.
 9. Compound of claim 1, in which R₃ is hydrogen and R₄ is ##STR51## in which Ar is phenyl and B is -NHR.
 10. Compound of claim 1, in which R₂ is benzyl, nitrobenzyl, methoxybenzyl, dimethoxybenzyl, or benzyloxymethyl, R₃ is hydrogen, and R₄ is ##STR52## in which Ar' is phenyl or substituted phenyl and Y is oxygen or sulfur.
 11. Compound of claim 1, in which R₁ is methyl, R₂ is p-nitrobenzyl, R₃ is hydrogen, and R₄ is ##STR53## in which Ar' is phenyl and Y is oxygen.
 12. Compound of claim 1, in which R₂ is -Si(R₁)₃, R₃ is hydrogen, and R₄ is -Si(R₁)₃.
 13. Compound of claim 1, in which R₂ is -Si(R₁)₃.
 14. Compound of claim 1, in which R₃ is hydrogen and R₄ is -Si(R₁)₃.
 15. Compound of claim 1, in which R₂ is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, amyl, hexyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, 2-iodoethyl, benzyl, p-nitrobenzyl, tetrahydropyranyl, succinimidomethyl, phthalimidomethyl, p-methoxybenzyl, cyanomethyl, 3,4-dimethoxybenzyl, p-nitrophenyl, 2,4-dinitrophenyl, 2,4,6-trinitrophenyl, bis(p-methoxyphenyl)-methyl, triphenylmethyl, benzhydryl, benzyloxymethyl, acetoxymethyl, propionoxymethyl, acetyl, propionyl, or phenacyl.
 16. Compound of claim 1, in which R₃ is hydrogen and R₄ is formyl, acetyl, propionyl, butyryl, valeryl, caproyl, azidoacetyl, cyanoacetyl, chloroacetyl, bromoacetyl, phenylacetyl, 2-thienylacetyl, 3-thienylacetyl, 2-furylacetyl, 3-furylacetyl, 2-pyrrolylacetyl, 3-pyrrolylacetyl, 4-chlorophenylacetyl, 3-trifluoromethylphenylacetyl, 4-hydroxyphenylacetyl, 3-tolylacetyl, 4-cumylacetyl, 4-methoxyphenylacetyl, 3-cyanophenylacetyl, 4-nitrophenylacetyl, phenoxyacetyl, thiophenylacetyl, pyridyloxyacetyl, p-nitrophenoxyacetyl, α-aminophenylacetyl, α-benzyloxycarbamidophenylacetyl, α-t-butoxycarbamidophenylacetyl, α-formyloxyphenylacetyl, α-cyanophenylacetyl, α-azidophenylacetyl, 3-sydnoneacetyl, 2-(1H-tetrazol-1-yl)acetyl, 2-nitrophenylthio, or 2-nitro-4-methoxyphenylthio.
 17. Compound of claim 1, in which R₃ is hydrogen and R₄ is ##STR54## in which Ar is phenyl, B is -NHR, and R is -Si(R₁)₃.
 18. Compund of claim 1, in which R₃ and R₄ taken together with the nitrogen atom to which they are bonded are phthalimido, succinimido, or 2,2-dimethyl-5-oxo-4-phenylimidazolidin-1-yl.
 19. Compound of claim 1, in which R₁ is ethyl, R₂ is 2,2,2-trichloroethyl, R₃ is hydrogen, and R₄ is ##STR55## in which Ar is phenyl.
 20. Compound of claim 12, in which R₁ is methyl.
 21. Compound of claim 1, in which R₁ is methyl, R₂ is p-nitrobenzyl, R₃ is hydrogen, and R₄ is ##STR56## in which Ar is phenyl, B is -NHR and R is trimethylsilyl.
 22. Compound of claim 1, in which R₁ is methyl, R₂ is 2,2,2-trichloroethyl, R₃ is hydrogen, and R₄ is ##STR57## in which Ar' is phenyl and Y is oxygen.
 23. Compound of claim 1, in which R₁ is methyl, R₂ is p-nitrobenzyl, R₃ is hydrogen, and R₄ is ##STR58## in which Ar is phenyl.
 24. Compound of claim 1, in which R₁ is methyl, R₂ is -Si(R₁)₃, R₃ is hydrogen, and R₄ is ##STR59## in which Ar'0 is phenyl and Y is oxygen. 